Liver development in embryos and regeneration in adults are characterized by regulated hepatocyte proliferation. This contrasts with the unregulated hepatocyte proliferation that accompanies many chronic hepatic diseases and hepatocellular carcinoma (HCC). While there is suggestion that common genetic pathways regulate both physiologic and pathologic hepatocyte proliferation, only a few studies in mammals illustrate this hypothesis. By forward genetic screening in zebrafish embryos combined with functional studies on liver regeneration in adults and expression analysis of human HCC samples, we have found that the ubiquitin-like, containing PHD and RING finger domains-1 (uhrf1) gene is essential for physiologic hepatocyte proliferation. We also believe that alterations in UHRF1 expression and/or regulation also contribute to deregulated proliferation in cancer. The work in this proposal will use a combination of zebrafish development and genetics, human cancer genomic analysis and mammalian tissue culture cell cycle studies and biochemistry to address 3 aspects of UHRF1 function in relation to hepatocyte proliferation.
In Specific Aim 1, we will examine the mechanism by which UHRF1 functions in regulating hepatocyte proliferation in zebrafish embryos.
In Specific Aim 2, we will elucidate how UHRF1 is regulated through phosphorylation by cyclin dependent kinase 2. The functional relevance of this phosphorylation will be assessed on cultured cells using biochemical and cell biological techniques.
In Specific Aim 3, we will determine the role of UHRF1 in hepatocarcinogenesis. By analysis of human HCC samples, we will evaluate the possibility that amplification of the UHRF1 locus contributes to its upregulation in cancer. Secondly, we will perform genetic and oncogenic studies in zebrafish and determine if UHRF1 is necessary and sufficient for hepatic tumor formation. In summary, this proposal will link together mechanisms that control hepatocyte proliferation in the embryo and during liver regeneration with those that control hepatocarcinogenesis. This proposal has direct relevance to the field of liver disease. Because the burden of liver disease remains enormous, the identification of genes that play critical roles in hepatocyte proliferation and in HCC progression are of significant scientific and clinical importance. The goal is to identify novel mechanisms of hepatocyte proliferation that can aid in the development of chemotherapeutic agents for use in management of patients with chronic liver diseases including HCC.
We are interested in how the liver develops, how it restores itself after injury and how liver cancer occurs. We believe that all three processes are linked and that understanding of normal liver growth will help in caring for patients with liver cancer. We believe that we have discovered a gene called UHRF1 that is involved in all the three processes and will study how it plays a role in each situation. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page
|Dhandapany, Perundurai S; Razzaque, Md Abdur; Muthusami, Uthiralingam et al. (2014) RAF1 mutations in childhood-onset dilated cardiomyopathy. Nat Genet 46:635-9|
|Mudbhary, Raksha; Hoshida, Yujin; Chernyavskaya, Yelena et al. (2014) UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell 25:196-209|
|Ersoy, Baran A; Tarun, Akansha; D'Aquino, Katharine et al. (2013) Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling. Sci Signal 6:ra64|
|Demchev, Valeriy; Malana, Geraldine; Vangala, Divya et al. (2013) Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization. PLoS One 8:e58084|
|Sadler, Kirsten C; Rawls, John F; Farber, Steven A (2013) Getting the inside tract: new frontiers in zebrafish digestive system biology. Zebrafish 10:129-31|
|Chu, Jaime; Loughlin, Elizabeth A; Gaur, Naseem A et al. (2012) UHRF1 phosphorylation by cyclin A2/cyclin-dependent kinase 2 is required for zebrafish embryogenesis. Mol Biol Cell 23:59-70|
|Mudbhary, Raksha; Sadler, Kirsten C (2011) Epigenetics, development, and cancer: zebrafish make their mark.. Birth Defects Res C Embryo Today 93:194-203|
|Tien, Amy L; Senbanerjee, Sucharita; Kulkarni, Atul et al. (2011) UHRF1 depletion causes a G2/M arrest, activation of DNA damage response and apoptosis. Biochem J 435:175-85|
|Zhao, Xiao; Monson, Christopher; Gao, Chuan et al. (2010) Klf6/copeb is required for hepatic outgrowth in zebrafish and for hepatocyte specification in mouse ES cells. Dev Biol 344:79-93|
|Feng, Suhua; Cokus, Shawn J; Zhang, Xiaoyu et al. (2010) Conservation and divergence of methylation patterning in plants and animals. Proc Natl Acad Sci U S A 107:8689-94|
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